Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Expression of CD94 and CD96 on CD8+ T cells early after allogeneic stem cell transplantation is predictive of subsequent disease relapse and survival

ABSTRACT: Allogeneic stem cell transplantation is used widely in the treatment of hematopoietic malignancy. However relapse of malignant disease is the primary cause of treatment failure and reflects loss of the immunological graft versus leukaemia effect. We studied the transcriptional and phenotypic profile of CD8+ T cells in the first month following transplantation and related this to risk of subsequent relapse. Single cell transcriptional profiling identified 5 discrete CD8+ T cell clusters. High levels of T cell activation and acquisition of a regulatory transcriptome were apparent in patients who went on to suffer disease relapse. A relapse-associated gene signature of 39 genes was then assessed in a confirmation cohort of 34 patients. High level expression of the inhibitory receptor CD94/NKG2A on CD8+ T cells within the first month was associated with 4.8 fold increased risk of relapse and 2.7 fold reduction in survival over the subsequent 4 years. Furthermore, reduced expression of the activatory molecule CD96 was associated with 2.2 fold increased risk of relapse and 1.9 fold reduction in survival. This work identifies CD94 and CD96 as potential targets for CD8-directed immunotherapy in the very early phase following allogeneic transplantation with the potential to reduce long term relapse rates and improve patient survival.

ORGANISM(S): blank sample Mus musculus Homo sapiens

PROVIDER: GSE185498 | GEO | 2022/07/31

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Expression of CD94 and CD96 on CD8+ T cells early after allogeneic stem cell transplantation is predictive of subsequent disease relapse and survival

Project description:Expression of CD94 and CD96 on CD8+ T cells early after allogeneic stem cell transplantation is predictive of subsequent disease relapse and survival

| PRJNA769281 | ENA

Signatures of GVHD and Relapse after Post-Transplant Cyclophosphamide Revealed by Immune Profiling and Machine Learning [17941R-18740R]

Project description:Lymphocyte subsets (CD8, CD4 Tconv, NK cells) were sorted from patients' peripheral blood obtained on day 28 after haploidentical-donor allogeneic bone marrow transplantation followed by posttransplant cyclophosphamide (PTCy), tacrolimus, and MMF as GVHD prophylaxis (NCT00796562). Cohort of patients developed GVHD, or remained GVHD-free. Cohort of patients developed disease relapse, or remained relapse-free. RNA-sequencing was performed to analyze the transcriptional landscape of alloresponse in post-PTCy breakthrough GVHD and relapse.

2021-09-28 | GSE182612 | GEO

Immune Escape after Allogeneic Hematopoietic Cell Transplantation in Pediatric Patients with Acute Myeloid Leukemia

Project description:Although allogeneic hematopoietic cell transplantation (allo-HCT) is curative for high-risk pediatric acute myeloid leukemia (AML), disease relapse remains the primary cause of post-transplant mortality. To identify pressures imposed by allo-HCT on AML cells that escape the graft-versus-leukemia effect, we evaluated immune signatures in bone marrow samples from four pediatric patients using a multimodal single-cell approach. Downregulation of MHC class II (MHC-II) expression observed at post-transplant relapse was most profound in progenitor-like blasts and was accompanied by correlative changes in transcriptional regulation. Dysfunction of activated NK cells and CD8+ T cell subsets at the time of relapse was evidenced by the loss of IFN-γ response, TNF-a signaling via NF-kB, and IL-2/STAT5 signaling. Clonotype analysis of post-transplant relapse samples revealed expansion of dysfunctional T cells and enrichment of T regulatory and T helper cells. Using novel computational methods, our results illustrate a diverse immune-related transcriptional signature in post-transplantation relapses not previously reported in pediatric AML.

2023-06-26 | GSE207104 | GEO

Azithromycin promotes relapse by disrupting immune and metabolic networks after allogeneic stem cell transplantation

Project description:Administration of azithromycin after allogeneic hematopoietic stem cell transplantation for hematological malignancies has been associated with relapse in a randomized phase 3 controlled clinical trial. Studying 240 samples from patients randomized in this trial is a unique opportunity to better understand the mechanisms underlying relapse, the first cause of mortality after transplantation. We used multi-omics on patients' samples to decipher immune alterations associated with azithromycin intake and post-transplant relapsed malignancies. Azithromycin was associated with a network of altered energy metabolism pathways and immune subsets, including T cells biased toward immunomodulatory and exhausted profiles. In vitro, azithromycin exposure inhibited T cells cytotoxicity against tumor cells and impaired T cells metabolism through glycolysis inhibition, mitochondrial genes downregulation, and immunomodulatory genes upregulation, notably SOCS1. These results highlight that azithromycin directly affects immune cells that favor relapse, which raises caution about long-term use of azithromycin treatment in patients at high risk of malignancies.

2022-08-22 | MTBLS406 | MetaboLights

Distinct biological and transcriptional features of FLT3-ITD variants in vitro and in vivo

Project description:Treatment of FLT3-ITD mutated AML remains a clinical challenge as this subset of patients show high incidence of relapse, even after allogeneic stem cell transplantation. Recently, we defined a molecular subset of FLT3-ITD mutations, located in the FLT3-tyrosine kinase domain 1 (TKD1). In multivariable analyses, insertion of ITD variants in the beta1-sheet (TKD1) was identified as an unfavorable prognostic factor for achievement of a complete remission relapse-free survival and overall survival independently of other prognostic factors such as allelic ratio. In the presented analysis we characterize ITD variants located in the TKD1. While transforming capacity and activation of downstream signaling nodes appears comparable to ‘classical’ ITD mutations located in the JM-domain, TKD1-ITDs reveal a distinct gene expression profile and confer decreased sensitivity to kinase inhibitor therapy in vitro and in vivo. This knowledge may impact clinical decisions in regard to TKI therapy versus allogeneic stem cell transplantation.

2014-12-31 | GSE56241 | GEO

scRNAseq of bone marrow (BM) T cells and hematopoietic stem and progenitor cells (HSPCs) of acute myeloid leukemia patients post allogeneic stem cell transplantation (alloSCT).

Project description:Gene expression profile at single cell level of bone marrow (BM) T cells and hematopoietic stem and progenitor cells (HSPCs) of acute myeloid leukemia patients post allogeneic stem cell transplantation (alloSCT) of patients in complete remission (CR) and relapse (REL).

2024-01-11 | GSE216187 | GEO

Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD mutant leukemia cells

Project description:Patients relapsing with FLT3-ITD mutant acute myeloid leukemia (AML) after allogeneic hematopoietic cell transplantation (allo-HCT) have a one-year-survival below 20%. We observed that sorafenib increased IL-15 production by FLT3-ITD+-leukemia cells, which synergized with the allogeneic CD8+T-cell response, leading to long-term survival in murine and humanized FLT3-ITD+AML models. Using IL-15 deficiency in recipient tissues or leukemia cells, IL-15 production upon sorafenib-treatment could be attributed to leukemia cells. Sorafenib treatment-related IL-15 production caused an increase in CD8+CD107a+IFN-γ+ T-cells with features of longevity (Bcl-2high/reduced PD-1-levels), which eradicated leukemia in secondary recipients. Mechanistically, sorafenib reduced ATF4 expression, thereby blocking negative regulation of IRF7-activation, which enhances IL-15 transcription. Consistent with the mouse data, IL-15 and pIRF7 levels increased in leukemic blasts of FLT3-ITD+AML patients upon sorafenib treatment. Analysis of 130 patients with FLT3-ITD-mutant AML relapsing after allo-HCT showed the highest complete remission-rate and median overall-survival-rate in the sorafenib/donor lymphocyte infusion (DLI) group compared to all other groups (chemotherapy, chemotherapy/DLI, sorafenib alone). Our findings indicate that the synergism of DLI and sorafenib is mediated via reduced ATF4 expression, causing activation of the pIRF7/IL-15-axis in leukemia cells. The sorafenib/DLI strategy therefore has the potential for an immune-mediated cure of FLT3-ITD-mutant AML- relapse, an otherwise fatal complication after allo-HCT.

2017-12-19 | GSE95770 | GEO

Project description:Leukemia relapse via genetic immune escape after allogeneic hematopoietic cell transplantation

| PRJNA1094436 | ENA

Leukemia relapse via genetic immune escape after allogeneic hematopoietic cell transplantation

Project description:Leukemia relapse via genetic immune escape after allogeneic hematopoietic cell transplantation

| PRJNA947751 | ENA

Leukemia relapse via genetic immune escape after allogeneic hematopoietic cell transplantation

Project description:Leukemia relapse via genetic immune escape after allogeneic hematopoietic cell transplantation

| PRJNA947752 | ENA